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Article

Synthesis and In Vitro Evaluation of C-7 and C-8 Luteolin Derivatives as Influenza Endonuclease Inhibitors

1
Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Gilead Sciences and IOCB Research Center, Flemingovo n. 2, 166 10 Prague, Czech Republic
2
Department of Organic Chemistry, Faculty of Science, Charles University, Hlavova 8, 128 00 Prague, Czech Republic
3
First Faculty of Medicine, Charles University, Kateřinská 1660, 121 08 Prague, Czech Republic
4
Institute of Molecular Genetics of the Czech Academy of Sciences, Vídeňská 1083, 140 00 Prague, Czech Republic
5
Department of Biochemistry, Faculty of Science, Charles University, Hlavova 8, 128 00 Prague, Czech Republic
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: Mattia Mori and Ilaria Vicenti
Int. J. Mol. Sci. 2021, 22(14), 7735; https://doi.org/10.3390/ijms22147735
Received: 26 May 2021 / Revised: 15 July 2021 / Accepted: 17 July 2021 / Published: 20 July 2021
(This article belongs to the Special Issue Antiviral Drug Targets: Structure, Function, and Drug Design)
The part of the influenza polymerase PA subunit featuring endonuclease activity is a target for anti-influenza therapies, including the FDA-approved drug Xofluza. A general feature of endonuclease inhibitors is their ability to chelate Mg2+ or Mn2+ ions located in the enzyme’s catalytic site. Previously, we screened a panel of flavonoids for PA inhibition and found luteolin and its C-glucoside orientin to be potent inhibitors. Through structural analysis, we identified the presence of a 3′,4′-dihydroxyphenyl moiety as a crucial feature for sub-micromolar inhibitory activity. Here, we report results from a subsequent investigation exploring structural changes at the C-7 and C-8 positions of luteolin. Experimental IC50 values were determined by AlphaScreen technology. The most potent inhibitors were C-8 derivatives with inhibitory potencies comparable to that of luteolin. Bio-isosteric replacement of the C-7 hydroxyl moiety of luteolin led to a series of compounds with one-order-of-magnitude-lower inhibitory potencies. Using X-ray crystallography, we solved structures of the wild-type PA-N-terminal domain and its I38T mutant in complex with orientin at 1.9 Å and 2.2 Å resolution, respectively. View Full-Text
Keywords: bio-isosterism; cross-coupling; endonuclease inhibitor; flavonoids; influenza; Mannich reaction; RNA polymerase bio-isosterism; cross-coupling; endonuclease inhibitor; flavonoids; influenza; Mannich reaction; RNA polymerase
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MDPI and ACS Style

Reiberger, R.; Radilová, K.; Kráľ, M.; Zima, V.; Majer, P.; Brynda, J.; Dračínský, M.; Konvalinka, J.; Kožíšek, M.; Machara, A. Synthesis and In Vitro Evaluation of C-7 and C-8 Luteolin Derivatives as Influenza Endonuclease Inhibitors. Int. J. Mol. Sci. 2021, 22, 7735. https://doi.org/10.3390/ijms22147735

AMA Style

Reiberger R, Radilová K, Kráľ M, Zima V, Majer P, Brynda J, Dračínský M, Konvalinka J, Kožíšek M, Machara A. Synthesis and In Vitro Evaluation of C-7 and C-8 Luteolin Derivatives as Influenza Endonuclease Inhibitors. International Journal of Molecular Sciences. 2021; 22(14):7735. https://doi.org/10.3390/ijms22147735

Chicago/Turabian Style

Reiberger, Robert, Kateřina Radilová, Michal Kráľ, Václav Zima, Pavel Majer, Jiří Brynda, Martin Dračínský, Jan Konvalinka, Milan Kožíšek, and Aleš Machara. 2021. "Synthesis and In Vitro Evaluation of C-7 and C-8 Luteolin Derivatives as Influenza Endonuclease Inhibitors" International Journal of Molecular Sciences 22, no. 14: 7735. https://doi.org/10.3390/ijms22147735

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